Introduction and Objective: The sarco-ER Ca2+ ATPase (SERCA2) pump maintains endoplasmic reticulum (ER) Ca2+ levels in the pancreatic β-cell. Previously, we demonstrated reduced SERCA2 expression in islets from human organ donors with type 2 diabetes (T2D) compared to islets from non-diabetic organ donors. Additionally, we have shown that heterozygous deletion of SERCA2 in mice (S2HET) leads to reduced whole body glucose tolerance and impaired islet glucose stimulated insulin secretion (GSIS) in response to diet-induced obesity. Because the ER is the major hub for lipid synthesis, we hypothesized that SERCA2 deficiency in the pancreatic β-cell may be associated with changes in lipid signaling and turnover that could impact insulin production and secretion.Methods: To test this hypothesis, islets isolated from wildtype (WT) and S2HET mice were treated with glucolipotoxic stress (GLT, 25mM glucose and 0.5mM palmitate) for 72 hours. GSIS was measured by ELISA and lipidomics were performed using LC-MS/MS.Results: GSIS assays showed reduced insulin secretion and an unexpected increase in insulin and proinsulin content in GLT-treated S2HET islets compared to WT islets. Analysis of lipid subclasses revealed reduced cholesterol, sphingomyelin, and glucosylceramide in GLT-treated S2HET islets and significant changes to sphingolipid acyl chain lengths generated by dihydroceramide synthases (CerS) 2 and 4.Conclusion: Taken together, our findings suggest that decreased SERCA2 expression during T2D conditions impairs insulin secretion and induces lipid remodeling. Characterizing this novel mechanism of β-cell dysfunction may provide valuable insight into the pathophysiology and treatment of T2D.
M. Hartley: Employee; Eli Lilly and Company. M.J. Pearson: Employee; Eli Lilly and Company. F. Syed: None. K.D. Roth: Employee; Eli Lilly and Company. T. Kono: None. C. Evans-Molina: Advisory Panel; DiogenX. Research Support; Bristol-Myers Squibb Company, Lilly Diabetes. Advisory Panel; Isla Technologies, Neurodon. Research Support; Neurodon.
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